Intermediates for spiro[2H-1,4-benzodioxepin-3(5H)4&#39;-piperidine] compounds

ABSTRACT

Spiro[2H-1,4-benzodioxepin-3(5H)4&#39;-piperidine and -3-pyrrolidine] compounds of the formula ##STR1## where the substituents are as defined herein, are useful in the treatment of hypertension in mammals. Such compounds, their use as antihypertensive agents, pharmaceutical compositions containing the compounds, intermediates and processes for preparing the compounds are provided.

This is a division of application Ser. No. 516,832, filed July 25, 1983,now U.S. Pat. No. 4,472,580, granted Sept. 18, 1984, which is a divisionof application Ser. No. 410,155, filed Aug. 20, 1982, now U.S. Pat. No.4,405,631, granted Sept. 20, 1983.

This invention relates to spiro [2H-1,4-benzodioxepin-3(5H)4'-piperidineand -3'-pyrrolidine]compounds. The compounds are useful in the treatmentof hypertension in mammals.

Hypertension in mammals may accompany many disorders, such as renaldisease, disease of the adrenal gland and toxemia of pregnancy. In mostpatients with high blood pressure, however, no primary disorder isevident and the condition is referred to as essential hypertension.

In controlled trials with patients afflicted with hypertension, it hasbeen found that hypertensive patients have more frequent cerebral andother cardiovascular accidents than those whose blood pressure has beenlowered by drugs. In addition, although hypertension may exist withoutinducing symptoms in the patient, it is more usual that clinicalmanifestations develop after elevated blood pressure has persisted forsome time. For example, hypertension has been associated with secondaryeffects, such as headache, dizziness, nose-bleeding, breathlessness onexertion, heart failure and stroke. Since these secondary effects maypresent a danger to life, it is desirable to lower the blood pressureand maintain it at a more nearly normal level.

A variety of antihypertensive drugs have been introduced for thetreatment of elevated blood pressure. Their development has representedan important advance in modern medicine. Intensive efforts are beingmade to develop new types of antihypertensive drugs and the need forsuch drugs continues.

This invention aids in fulfilling this need in the art by providingcompounds of the formula ##STR2## wherein R₁ is a C₃ or C₄ branched orstraight chain alkyl or alkenyl group or a C₄ -alkynyl group terminallysubstituted by one or two substituents independently selected from thegroup consisting of ##STR3## where

Y and Z are the same or different and are independently selected fromthe group consisting of H, Cl, F, Br, I, --NO₂, --CF₃, C₁ to C₄ straightchain alkyl, alkoxy containing C₁ to C₄ straight chain alkyl, acyl or--NH₂ ;

each R₅ substituent is independently selected from the group consistingof ##STR4##

R₂ is hydrogen when n=0 or R₂ is hydrogen or a C₁ to C₃ straight chainalkyl group when n=1;

R₃ is hydrogen or a C₁ to C₃ straight chain alkyl group;

R₄ is hydrogen or a C₁ to C₃ straight chain alkyl group;

m is zero, 1 or 2;

X is Cl, F, Br, I, --NO₂, --CF₃, --NR₆ R₇, ##STR5## C₁ to C₆ branched orstraight chain alkyl, --CN, --O--R₆, --SR₇, --SO₃ R₇, ##STR6## --NHCOR₈,--SO₂ R₉ or --SOR₉ where

R₆ is hydrogen or a C₁ to C₆ straight chain alkyl group,

R₇ is hydrogen or a C₁ to C₆ straight chain alkyl group,

R₈ is a C₁ to C₆ branched or straight chain alkyl group,

R₉ is a C₁ to C₆ straight chain alkyl group; provided that when m=2, theX-substituents can be the same only when X is selected from the groupconsisting of H, Cl, F, Br, I, C₁ to C₆ branched or straight chain alkylor --O--R₆ ;

n is zero or 1;

and the pharmaceutically acceptable salts thereof. It is to beunderstood that when R₁ is a C₄ -alkynyl group, the acetylenic bond isbetween carbon atom numbers 2 and 3 of the group, i.e., ##STR7##

In the preferred embodiment of this invention, the compounds of theinvention are represented by the following formula ##STR8## wherein R₁is a C₄ branched or straight chain alkyl or alkenyl group terminallysubstituted by p-fluorophenyl, bis-phenyl or bis-p-fluorophenyl groups;or R₁ is ##STR9## where R₂, R₃ and R₄ are independently selected fromhydrogen and --CH₃ ;

X is H, Cl, F, Br, I, --NO₂, --CH₃ or ##STR10## R₅, Y and Z are asdefined above; m is zero, 1 or 2;

n is zero or 1;

provided that, when m=2, the X-substituents can be the same only when Xis selected from the group consisting of H, Cl, F, Br, I, --CH₃ and--OCH₃

and the pharmaceutically acceptable salts thereof.

The particularly preferred compounds of this invention can berepresented by the formula ##STR11## R₃ is H or --CH₃ ; X is H, Cl, F orBr;

and the pharmaceutically acceptable salts thereof.

These compounds are particularly preferred because of their relativeease of manufacture and because they exhibit relatively highantihypertensive activity in laboratory tests on animals.

This invention also provides compounds of the following formulae, whichare useful intermediates in the preparation of the pharmaceuticallyactive compounds of the invention: ##STR12## where X and m are aspreviously defined;

R is hydrogen or a methyl, acyl or benzyl group; and

HAL is chlorine or fluorine.

This invention also provides processes for preparing the compounds ofthis invention.

Further, this invention provides a method of alleviating hypertension ina mammal by administering to a mammal a pharmaceutically active compoundof the invention in an amount sufficient to reduce the blood pressure ofthe mammal.

Finally, this invention provides a pharmaceutical composition comprisinga pharmaceutically active compound of the invention and apharmaceutically acceptable carrier therefor.

The preparation of the compounds of this invention will now be explainedwith reference to the Figures, which are schematic diagrams depictingvarious routes of synthesis of piperidine derivatives of the invention.It will be understood that similar techniques can be employed tosynthesize the pyrrolidine derivatives of the invention.

Referring to FIG. 1, the starting reactant is an N-substituted-4-piperidone of formula (1), which is commercially available or can beprepared using well-known techniques for synthesizing organic compounds.The substituent R shown in the Figure can typically be a methyl, acyl orbenzyl group. The piperidone of formula (1) can be reacted intetrahydrofuran (THF) with an ammonical solution of sodium acetylide toobtain a 1-substituted-4-ethynyl-4-piperidinol of formula (2). Theresulting 1-substituted-4-ethynyl-piperidinol can be reacted with asubstituted or unsubstituted o-halobenzylchloride of formula (3) insolution in the presence of a base, such as potassium t-butoxide orsodium hydride, to yield a1-substituted-4-ethynyl-4-(o-halobenzyloxy)-piperidine of formula (4).Substituted and unsubstituted compounds of formula (3) are also readilyavailable or can be prepared using conventional techniques. The halogroup in the compounds of formula (3) is identified in FIG. 1 as HAL andis chlorine or fluorine, the latter being preferred.

Hydrolysis converts the ethynyl group in the compound of formula (4) toan oxoethyl group. This is achieved by reacting the compound of formula(4) with water catalyzed by mercuric sulphate in an acidic medium, suchas methanol/sulphuric acid. The resulting4-(1-oxoethyl)-4-(o-halobenzyloxy)-piperidine of formula (5) isisolated. If the substituent R in the compound of formula (4) is an acylgroup, this group is hydrolyzed so that R is hydrogen in the compound offormula (5).

The keto group of the compound of formula (5) is reduced to a hydroxylgroup in solution by sodium borohydride, for example, to form a4-(1-hydroxyethyl)-4-(o-halobenzyloxy)-piperidine of formula (6).

The alcohol of formula (6) can be cyclized to form the dioxepin ringsystem of the compounds of the invention. The cyclization can be carriedout in the presence of a base, such as potassium t-butoxide or sodiumhydride, in a solvent, such as dimethyl sulfoxide (DMSO) or THF, attemperatures from room temperature to reflux temperature. If thesubstituent R in the alcohol of formula (6) is hydrogen, then thecompound of formula (8) in FIG. 1 will be obtained. If the substituent Ris a methyl, acyl or benzyl group, then the cyclization reaction willproduce a compound of formula (7).

The compound of formula (8) can be obtained from the compound of formula(7) by removing the methyl, acyl or benzyl group using conventionaltechniques. For example, if R is methyl, the compound of formula (7) canbe converted to a carbamate, such as by reaction with ethylchloroformate, followed by hydrolysis with a base, such as potassiumhydroxide. The same technique can be employed if R is a benzyl group.Alternatively, the benzyl group can be removed by catalytichydrogenation, such as by use of a palladium on carbon catalyst. If thesubstituent R is an acyl group, the acyl group will usually be removedduring the formation of the compound of formula (5), but similarhydrolysis of the compound of formula (7) will yield the compound offormula (8).

The substituent R₁ can be introduced into the compounds by alkylation ofthe piperidine nitrogen of the compound of formula (8) with substitutedalkyl, alkenyl or alkynyl halides or sulfonate esters to obtain acompound of formula (9). The reaction can be carried out in an aproticsolvent, such as N,N-dimethylformamide (DMF) or n-butyl acetate. Thereaction is carried out in the presence of an acid scavenger, such aspotassium carbonate or sodium carbonate. Sodium bicarbonate can beemployed with some base sensitive materials or olefins. A catalyst, suchas potassium iodide, can also be employed. The reaction is typicallycarried out at a temperature from about ambient to about 125° C.,preferably about 20° C. to about 90° C. Typically, the reaction timewill be about 45 minutes to about 18 hours. While the reactants can beemployed in equimolar amounts, the alkyl, alkenyl or alkynyl halide isoften used in excess amount. Generally, the alkyl, alkenyl and alkynylhalides will not exceed about 10% molar excess of the compound offormula (8). If the R₁ substituent contains an olefinic group, it may benecessary to add alkylating agent to the reaction medium to replaceportions of the agent that may undergo side reactions. The alkylatingreaction can be carried out in air or under inert gas, such as anitrogen blanket. It is preferable to mildly agitate the reactionmixture during the course of the reaction. The alkylating agentsemployed in this invention are either commercially available or can beprepared by conventional techniques.

In some cases it is necessary to subject the piperidine of formula (9)to further processing to obtain the desired R₁ -substituent. Forexample, compounds of the invention in which R₁ is ##STR13## where Y isas previously defined, can be prepared by alkylation of the free base offormula (8) as previously described. The resulting compound can then bereacted with acidified aqueous alcohol solution at elevated temperatureto form a piperidine of the invention in which R₁ is ##STR14## Treatmentof the keto group in substituents R₁ with a reducing agent, such assodium borohydride, in solution results in the formation of compounds ofthe invention in which R₁ is ##STR15## The resulting hydroxyl-containingsubstituent can be converted to an ether-containing substituent of theformula ##STR16## where Y and Z are previously defined, by formation ofan anion with, for example, sodium hydride, and then reaction with anaryl halide, for example, 1,4-difluorobenzene.

Once the compounds of formula (7) or (8) are obtained, substituent --Xcan often be readily introduced into the compounds using conventionaltechniques. Addition of substituent --X to the benzodioxepin ring systemis facilitated by the presence of the oxygen in the 1-position of thedioxepin ring, which functions as an ortho/para-directing substituent.As an example of a reaction for introducing substituent --X into thecompounds of the invention a salt of the compound of formula (7) or (8)can be reacted with N-chlorosuccinimide or N-bromosuccinimide insolution. A compound of formula (7) or (8) in which the substituent --Xis chlorine or bromine, respectively, will be obtained. Other similarlywell-known reactions can be employed to introduce other species of theX-substituent into the compounds.

When the substituent R₂ is other than hydrogen the R₂ substituent isconveniently introduced into the compounds of the invention during anearly stage of preparation. For example, R₂ can be substituted onto thepiperidone of formula (1) by alkylation via an enamine. Thus, thepiperidone can be converted to enamine, which can be alkylated. Otherstandard methods, such as formation of a hydrazone followed byalkylation and hydrolysis to form a ketone, can also be employed.

Compounds of the invention in which R₄ is other than hydrogen can alsobe prepared by introducing the R₄ substituent at an early stage of thesynthesis. For instance, the substituent R₄ can be introduced as part ofthe compound of formula (3). Instead of the benzyl chloride (3), acompound of the formula ##STR17## can be utilized where X, m, HAL and R₄are as previously defined. Compounds of this type can be readilyprepared using conventional techniques. When the substituent R₃ is otherthan hydrogen or --CH₃, the R₃ substituent is conveniently introducedinto the compounds of the invention at an intermediate stage of thesynthesis. For example, addition of a Grignard reagent to the aldehydeof formula (15) in FIG. 2 and hydrolysis of the resulting intermediatewill form an alcohol analogous to the compound of formula (6). Thealdehyde of formula (15) can be synthesized as shown or by other methodsknown in the art. In addition, other well-known methods for adding alkylgroups to aldehydes and ketones can be employed.

It will be apparent from FIG. 1 that the reaction sequence depictedresults in the preparation of compounds of the invention in which thesubstituent R₃ is a methyl group. Corresponding compounds in which R₃ ishydrogen can be prepared according to the general reaction schemedepicted in FIG. 2. In this case, 1,3-dithiane of formula (1) is reactedwith n-butyllithium to form a lithium salt of formula (11). The lithiumsalt is then reacted with a commercially available methyl-substituted4-piperidone of formula (12) in solution in a solvent, such astetrahydrofuran, to form the alcohol of formula (13). The alcohol (13)is reacted with a substituted or unsubstituted o-halobenzylchloride offormula (3) as previously described. This reaction can be carried out ina solvent, such as tetrahydrofuran, in the presence of a base, such aspotassium t-butoxide, to form the compound of formula (14). The ketoneof formula (15) is formed by reacting the compound of formula (14) withmercuric oxide in the presence of boron trifluoride in solution. Thealcohol of formula (16) is prepared from the ketone (15) using thetechnique described in connection with the preparation of the alcohol offormula (6) in FIG. 1.

The alcohol of formula (16) can then be cyclized as previously describedto form the compound of formula (17). If the tertiary amino group isconverted to a secondary amino group, compounds of the inventioncontaining the substituent R₁ can be readily prepared by alkylation ofthe piperidine nitrogen with substituted alkyl, alkenyl or alkynylhalides or sulfonate esters, as previously described. Conversion to thesecondary amino group can be accomplished by reacting the compound offormula (17) with phenylchloroformate to convert the methyl group to aphenoxycarbonyl group as shown in formula (18), which can then beconverted to the free base of formula (19) by reaction with aqueoussodium hydroxide in a solvent, such as methanol.

It will be understood that this invention includes the compounds of theinvention in all of their stereoisomeric forms, including theirenantiomers and diastereomers. This invention also contemplates usingmixtures of such forms in the treatment of hypertension in mammals.

It will also be understood that the compounds of the invention andintermediates for their preparation can exist in either the form of afree base or as an acid addition salt. For example, it is oftenconvenient to isolate compounds from reaction mixtures by precipitatingthem from solution by the addition of an acid having a pharmaceuticallyacceptable anion. The precipitate can be recovered and purified, and theresulting salt converted to its free base by addition to an alkalinemedium.

Compounds of this invention are useful as antihypertensive agents due totheir ability to depress blood pressure in mammals. Antihypertensiveactivity is measured in the spontaneous hypertensive rat by the indirecttail cuff method described by A. Schwartz, Ed., Methods in Pharmacology,Vol. I, page 135, Appleton Century Crafts, New York (1971). In thisprocedure, a group of five animals is treated orally with the drug forthree days in relation to a control group of the same number. The dropin blood pressure is measured on the third day following administration.The antihypertensive activity is expressed as mm Hg decrease in meanarterial blood pressure. Some of the compounds of this invention weretested according to this spontaneous hypertensive rat (SHR) test andwere found to produce the results shown in Table I. The dose isindicated as mg of the compound per kg body weight by peroral (PO)administration.

                                      TABLE I                                     __________________________________________________________________________     ##STR18##                                                                    Compound of                     SHR  Dose                                     Example                                                                              Salt X R.sub.1           mm Hg                                                                              mg/kg PO                                 __________________________________________________________________________    36     C.sub.2 H.sub.2 O.sub.4                                                            H H                 -42  50                                        8     C.sub.2 H.sub.2 O.sub.4                                                            H                                                                                ##STR19##        -102 50                                        9     C.sub.4 H.sub.4 O.sub.4                                                            H                                                                                ##STR20##        -34  50                                       10     C.sub.4 H.sub.4 O.sub.4                                                            H                                                                                ##STR21##        -18  50                                       11     C.sub.2 H.sub.2 O.sub.4                                                            H                                                                                ##STR22##        -17  50                                       12     C.sub.4 H.sub.4 O.sub.4                                                            H                                                                                ##STR23##        -20  50                                       16     C.sub.2 H.sub.2 O.sub.4                                                            Cl                                                                               ##STR24##        -47  50                                       17     C.sub.2 H.sub.2 O.sub.4                                                            Cl                                                                               ##STR25##        -43 -23                                                                            50 3                                     14     HCl  H                                                                                ##STR26##        -34  50                                       18     C.sub.2 H.sub.2 O.sub.4                                                            Cl                                                                               ##STR27##        -41   0.3                                     19     C.sub.2 H.sub.2 O.sub.4                                                            Cl                                                                               ##STR28##        -43  10                                       23          H                                                                                ##STR29##        -31  10                                       20     HCl  Cl                                                                               ##STR30##        -15  50                                       22     C.sub.2 H.sub.2 O.sub.4                                                            H                                                                                ##STR31##        -24  50                                       21     C.sub.2 H.sub.2 O.sub.4                                                            Br                                                                               ##STR32##        -74 -63                                                                            50 3                                     15     C.sub.2 H.sub.2 O.sub.4                                                            H                                                                                ##STR33##        -27  50                                       41     HCl  F                                                                                ##STR34##        -34  50                                       42     HCl  F                                                                                ##STR35##        -126 50                                       __________________________________________________________________________

The above data illustrates that compounds of the present invention areuseful for the treatment of hypertension when administered to mammals.Compounds of the invention compare favorably with the well-known drugα-methyl dopa which, in a similar test, gives an SHR value -40 mm Hgwhen administered at 50 mg/kg PO for five days.

Typically, the dose of the compounds of the invention will be from about0.1 to about 50 mg/kg of body weight per day.

The compounds of the present invention may be administered in apharmaceutically effective amount to a subject by a convenient route,such as orally, intramuscularly, intravenously, subcutaneously orintraperitoneally. The preferred route of administration is oral, forexample, with an inert diluent or with an edible carrier or in gelatin,capsules or tablets.

For the purpose of oral therapeutic administration, the active compoundsof this invention may be incorporated with excipients and used in theform of tablets, troches, capsules, exilirs, suspensions, syrups,wafers, chewing gum and the like. These preparations should contain atleast about 0.5% by weight of active compound, but the amount of activeingredient may be varied depending on the particular form and maytypically be between about 7 to about 70% by weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained. Preferred compositions in preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between about 1 and about 200 mg of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing adjuvants: a binder, such as gum tragacanth or gelatin; anexcipient, such as starch or lactose; a disintegrating agent, such asalgenic acid, potato starch and the like; a lubricant, such as magnesiumstearate; a sweetening agent, such as sucrose or saccharine, or aflavoring agent, such as peppermint, methylsalicylate or orangeflavoring. When the dosage unit form is a capsule, it may contain inaddition to materials of the above type, a liquid carrier, such as afatty oil. Other dosage unit forms may contain various other materialsthat modify the physical form of the dosage unit, for example, coatings.Thus, tablets or pills may be coated with sugar, shellac, or both. Asyrup may contain, in addition to the active compounds, sucrose as asweetening agent, preservatives, colorings, and flavors. Materialsemployed in preparing these various compositions must bepharmaceutically pure and non-toxic in the amounts utilized.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution orsuspension. These preparations should contain at least about 0.1% byweight of active compound, but may be varied to typically contain about0.5 to about 30% of the weight thereof. The amount of active compound insuch compositions is such that a suitable dosage will be obtained.Preferred compositions in preparations according to the presentinvention are prepared so that a parenteral dosage unit contains betweenabout 0.5 to about 100 mg of active compound.

The solutions or suspensions may also include the following components:a sterile diluent, such as water, for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents, such as benzyl alcohol ormethyl paraben; antioxidants, such as ascorbic acid or sodium bisulfite;chelating agents, such as ethylenediamine tetraacetic acid; buffers,such as acetates, citrates or phosphates; and agents for the adjustmentof tonicity, such as sodium chloride or dextrose. Parenteralpreparations can be enclosed in ampules, disposable syringes or multipledose vials made of glass or plastic.

The compounds of the invention, while effective in themselves, may beformulated and administered in the form of their pharmaceuticallyacceptable addition salts for purposes of stability, convenience ofcrystallization, increased solubility and the like. Such salts includethe salts of inorganic acids, such as hydrochloric acid, hydrobromicacid, sulfuric acid and nitric acid. Salts of organic acids, such ascitric, fumaric, maleic and tartaric acids, can also be employed.

This invention will now be described in greater detail in the followingExamples.

EXAMPLE 1 1-Acetyl-4-ethynyl-4-piperidinol

To 350 ml of liquid ammonia was added 0.06 g of ferric nitrate. When theferric nitrate dissolved, 1.0 g of sodium was added. The mixture wasstirred until a black precipitate formed. To the mixture was then added3.25 g of sodium. The solution was stirred until the mixture turned grayafter which acetylene was bubbled through the reaction for 2 hrs. To themixture was then added 25 g (0.177 mol) of N-acetyl-4-piperidone in 100ml of dry THF. The mixture was subsequently stirred for 3 hrs. duringwhich time acetylene was bubbled through. The reaction was then quenchedby addition of 10 g (0.187 mol) of ammonium chloride. The ammonia wasallowed to evaporate overnight. To the mixture was then added 75 ml ofsaturated ammonium nitrate and 40 ml of 25% ammonium hydroxide. Themixture was then extracted twice with chloroform, dried over potassiumcarbonate, filtered and the solvent evaporated to provide a white solid.The solid was washed with anhydrous ether and dried. The crude yield of1-acetyl-4-ethynyl-4-piperidinol was 17.9 g (0.107 mol, 60.6%).Recrystallization from ethyl acetate provided analytically purematerial, m.p. 132°-134° C. The material appeared pure by TLC (silica;2% methanol/chloroform), R_(f) =0.2; (silica; 10%methanol/dichloromethane), R_(f) =0.4, IR (chloroform), ¹ H-NMR (CDCl₃)and MS (MH⁺ =168) are consistent with the assigned structure.

ANALYSIS. Calculated for C₉ H₁₃ NO₆ : 64.65%C, 7.83%H, 8.38%N. Found:64.38%C, 7.81%H, 8.40%N.

EXAMPLE 2 1-Acetyl-4-ethynyl-4-(2-fluorophenylmethoxy)piperidine

Sodium hydride (39.98 g as a 50% mineral oil suspension, 883 mmole) wassuspended in dry DMF (500 ml). 1-Acetyl-4-ethynyl-4-hydroxypiperidine(126.5 g; 758 mmole), dissolved in 500 ml of DMF, was added dropwise tothe sodium hydride suspension at such a rate as to maintain the solventtemperature below 30° C. After evolution of hydrogen had ceased,2-fluorobenzylchloride (120.8 g; 99 ml; 833 mmole), dissolved in 200 mlof DMF, was added dropwise, maintaining the temperature below 25° C.After allowing the mixture to react for 3 hours, 2 l. of water was addedto quench the reaction. The mixture was extracted with ether and thecombined ether extracts were back extracted with 5% hydrochloric acid.The organic phase was finally extracted with saturated aqueous sodiumchloride and dried over anhydrous potassium carbonate. The mixture wasfiltered and the volatile components removed in vacuo. A residue ofmaterial, slightly impure by TLC, remained (193 g; 700 mmole; 84.3%). A10 g sample was purified by preparative high performance liquidchromatography (HPLC) using hexane:ethylacetate (2:1) and finallyethylacetate as the effluents on silica gel. The residue was an oilwhich crystallized upon standing. Recovery was 7 g of material whichappeared pure by TLC on silica gel in hexane:ethylacetate (2:1), R_(f)=0.1 and in chloroform:methanol (9:1), R_(f) =0.6. MS (ci MH⁺ =276),NMR-CDCl₃ and IR-CHCl₃ are consistent with the structure, m.p.=59°-62°C.

ANALYSIS. Calculated for C₁₆ H₁₈ FNO₂ : 69.79%C, 6.60%H, 5.09%N. Found:69.72%C, 6.56%H, 4.88%N.

EXAMPLE 3 4-(1-Oxoethyl)-4-(2-fluorophenylmethoxy)piperidine oxalate

The compound 1-acetyl-4-ethynyl-4-(2-fluorophenylmethoxy)piperidine (262g; 950 mmole) was dissolved in 1600 ml of methanol: water (1:1) in a3-necked round bottomed flask equipped with mechanical stirrer;thermometer, reflux condenser and nitrogen line. A solution of 180 ml ofconcentrated sulfuric acid dissolved in 200 ml of water was added to thestirred solution. The mixture was heated to reflux and stirred at thattemperature for 3 hrs. Hydrolysis of the acetyl function was monitoredby infra-red spectra of aliquots of the reaction. The reaction mixturewas cooled and 73 g of mercuric sulfate was added and the temperaturewas raised to reflux again. Hydrolysis to the ketone was monitored byinfrared spectra as well. After 3 hrs, at reflux, the reaction wasdetermined to be complete. The mixture was cooled and filtered. Thefiltrate was made basic (pH=8.5) with 50% sodium hydroxide and wasextracted several times with chloroform. The organic layer was driedover anhydrous magnesium sulfate and filtered. The solvent was removedunder vacuum and the residue was chromatographed on 500 g of aluminapacked in ether. The compound was eluted with ether:ethanol (1:1) withthe collection of 125 ml fractions. Those containing the material (6-24)were combined and the oxalate salt was precipitated, which was filtered,washed with anhydrous ether and dried (42 g, 123 mmole, 13% yield). A 7g sample was recrystallized from ethanol resulting in 2 g of4-(1-oxoethyl)-4-(2-fluorophenylmethoxy)piperidine oxalate in the firstcrop. This material appeared pure by thin layer chromatography on silicagel in chloroform:methanol (9:1), R_(f) =0.30 and hexane:THF (1:1),R_(f) =0.10. MS (ci MH⁺ =252), NMR-DMSO-d₆ and IR-KBr are consistentwith the structure, m.p.=154°-155° C.

ANALYSIS. Calculated for C₁₆ H₂₀ FNO₆ : 56.79%C, 5.92%H, 4.10%N. Found:56.60%C, 5.81%H, 4.01%N.

EXAMPLE 4 4-(1-Hydroxyethyl)-4-(2-fluorophenylmethoxy)piperidine oxalate

The compound 4-(1-oxoethyl)-4-(2-fluorophenylmethoxy)piperidine oxalate(10.00 g, 29.00 mmole) was converted to its free base with saturatedaqueous sodium bicarbonate and extracted into chloroform. The organiclayer was dried over anhydrous magnesium sulfate, filtered and thechloroform was removed in vacuo. The residue was dissolved in 20 ml ofmethanol and added dropwise to a suspension of 2.76 g of asodiumborohydride (73.00 mmole) in 30 ml of methanol. This wasmaintained at 20° C. (using an ice bath) and was allowed to reactovernight at ambient temperature under nitrogen. The reaction wasquenched with 5 ml of 10% hydrochloric acid. After being stirred for 1hr., the solvent was removed under vacuum and the solid residue wasdissolved in water. The solution was made basic (pH=10) with saturated,aqueous sodium bicarbonate and the mixture was extracted withchloroform. After drying over anhydrous magnesium sulfate, thechloroform solution was filtered, diluted with an equal volume ofanhydrous ether and the product precipitated as its oxalate salt. Theprecipitate was recrystallized from 2-propanol resulting in 2.90 g of4-(1-hydroxyethyl)-4-(2-fluorophenylmethoxy)piperidine oxalate (8.50mmole, 28.15%) in the first crop. This material appeared pure by thinlayer chromatography on silica gel in chloroform:methanol (1:1), R_(f)=0.1 and 2-propanol:ammonium hydroxide (7:3) R_(f) =0.7. MS (ci MH⁺=254), NMR-DMSOd₆ and IR-KBr are consistent with the structure,m.p.=145°-150° C.

ANALYSIS. Calculated for C₁₆ H₂₂ FNO₆ : 55.96%C, 6.47%H, 4.08%N. Found:56.15%C, 6.38%H, 4.13%N.

EXAMPLE 5 2-Methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride

The compound 4-(1-hydroxyethyl)-4-(2-fluorophenylmethoxy)piperidineoxalate (55.4 g, 0.162 mole) was converted to its free base and wasextracted into chloroform. The combined extracts were loaded onto a 500g alumina column packed in diethyl ether. Final elution with diethylether:ethanol (1:1), removal of all solvents and trituration with hexaneafforded 33 g (0.130 mole) solids after vacuum drying. Recovery=80.5%.The solids were dissolved in 290 ml dimethyl sulfoxide (DMSO). A secondmixture was prepared by suspending a hexane-washed 50% mineral oildispersion of NaH (6.6 g, 0.137 mole) in 340 ml dry DMSO. The secondmixture was heated to 60°-70° C. for 1 hr. When evolution of hydrogenceased, the mixture was cooled to 25° C. and the first solution addeddropwise thereto while maintaining the temperature at about 25° C. Whenaddition was complete, the mixture was heated to 70° C. for 1 hr. GLCshowed the reaction to be substantially complete. The reaction mixturewas quenched with K₂ CO₃ /H₂ O and extracted with diethyl ether. Theextract was dried, and the hydrochloride salt was precipitated and driedat 50° C. in vacuo. Yield=32.2 g (0.12 mol), 91.9%.

EXAMPLE 67-Chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochlorid

The compound2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride(0.57 g, 2.12 mmole) was dissolved in 20 ml methanol and stirred with0.32 g of N-chlorosuccinimide (2.33 mmole). The mixture was heated atreflux for 45 min. after which the reaction was determined to be 98%complete by GLC (3%, ASI, 200° C., flow=45 ml/min). The volume ofmethanol was reduced by distillation and upon cooling the productcrystallized. The reaction yielded 0.47 g of7-chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride(1.55 mmole, 73.11%) which appeared pure by TLC on silica gel in2-propanol:ammonium hydroxide (10:1), R_(f) =0.4 and inchloroform:methanol (1:1), R_(f) =0.1. MS (ci MH⁺ =268), NMR-DMSO-d₆,CMR-DMSO-d₆ and IR-KBr are consistent with the structure, m.p. 274°-276°C., d.

ANALYSIS. Calculated for C₁₄ H₁₉ ClNO₆ : 55.27%C, 6.31%H, 4.60%N. Found:54.94%C, 6.24%H, 4.54%N.

EXAMPLE 77-Bromo-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride

The compound2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperdine]hydrochloride (3.4g, 12.64 mmole) was dissolved in 200 ml of methanol along with 2.47 g ofNBS (13.9 mmole). The mixture was allowed to react for 45 min. afterwhich time reaction was determined to be complete by GLC (OV 225, 200°C., 30 ml/min, t_(R) =4.52). The methanol was removed in vacuo and theresidue was suspended in saturated aqueous Na₂ CO₃. The products wereextracted with chloroform and upon removal of solvent, in vacuo, thereresulted a solid material. The solid was dissolved in ether and thehydrochloride salt precipitated. The material was recrystallized frommethanol resulting in 2.5 g of7-bromo-2-methylspiro[2H-1,4-benzodioxpin-3(5H)4'-piperidine]hydrochloridewhich appeared pure by TLC on silica gel in 2-propanol:ammoniumhydroxide (9:1), R_(f) =0.4 and in chloroform:methanol (1:1), R_(f)=0.1. Mass Spec (M.sup. + =311, 313; 1/1), NMR-DMSO-d₆ and IR-KBr areconsistent with the structure, m.p.=290°-293° C., d.

ANALYSIS. Calculated for C₁₄ H₁₉ BrClNO₂ : 48.22%C, 5.50%H, 4.02%N.Found: 48.13%C, 5.52%H, 3.99%N.

EXAMPLE 81'-[4,4-Bis-(4-fluorophenyl)butyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate

The compound2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate (3.9 g,12.2 mmole) was converted to its free base and was extracted intochloroform. The combined extracts were dried over magnesium sulate andwere filtered. The filtrate was reduced in volume in vacuo. The residuewas dissolved in 25 ml of DMF and was stirred with 2.6 g of4,4-bis-(4-fluorophenyl)butylchloride (13.4 mmole). To the resultantmixture was added 2.5 g of milled anhydrous potassium carbonate and 16mg of potassium iodide. The mixture was heated at 100° C. for 6 hr.,after which time the reaction was determined complete by TLC. Themixture was cooled to ambient temperature and quenched with 100 mlwater. The products were extracted with ether and the solvent wasremoved in vacuo. The residue was loaded onto an 80 g alumina columnpacked in ether. The products were eluted in 30 ml fractions. Thedesired compound was found in fraction numbers 2 and 3. The fractionswere combined and the oxalate salt was precipitated, yielding 3.0 g(5.28 mmole 43.32%) of1'-[4,4-bis-(4-fluorophenyl)butyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate.The products were recrystallized from 2-propanol/methanol resulting in acrystalline material which appeared pure by TLC on silica gel inchloroform:methanol (9:1), R_(f) =0.7 and in dichloromethane:2-propanol,R_(f) =0.4. Mass Spec (ci MH⁺ =478), NMR-DMSO-d₆ and IR-KBr areconsistent with the structure, m.p.=213°-214° C. (d).

ANALYSIS. Calculated for C₃₂ H₃₅ F₂ NO₆ : 67.70%C, 6.23%H, 2.47%N.Found: 67.51%C, 6.18%H, 2.29%N.

EXAMPLE 92-Methyl-1'-[3-(2-(4-fluorophenyl)-1,3-dioxolan-2-yl]-propyl]spiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]maleate

The compound2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate (5 g, 15.5mmole) was converted to its free base and dried. The residue wasdissolved in 50 ml of DMF and stirred with 4.2 g ofγ-chloro-4-fluorobutyrophenone ethylene ketal (17.1 mmole), 5 g ofpotassium carbonate (anhydrous, milled) and 25 mg of potassium iodide.The mixture was heated to 100° C. under N₂ for 2 hrs. The reaction wasdetermined complete by TLC. After cooling to ambient temperature, themixture was quenched with water and was extracted with ether. Theorganic layers were combined and back extracted with saturated brine.The solvent was removed in vacuo and the residue loaded onto a 100 galumina column packed in ether. Fractions of 50 ml of ether were elutedand the desired material was found in numbers 2-4. These fractions werecombined and the maleate salt was precipitated. The solids wererecrystallized from 2-propanol yielding 3.1 g of2-methyl-1'-[3-[2-(4-fluorophenyl)-1,3-dioxalan-2-yl]propyl]spiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]maleate(5.6 mmole, 36%), which appeared pure by TLC on silica gel inchloroform:methanol (9:1), R_(f) =0.4 and in dichloromethane:2-propanol(1:1), R_(f) =0.5. MS (ci MH⁺ =442), NMR-DMSO-d₆ and IR-KBr areconsistent with the structure, m.p.=154°-156° C.

ANALYSIS. Calculated for C₃₀ H₃₆ FNO₈ : 64.61%C, 6.52%H, 2.51%N. Found:64.39%C, 6.45%H, 2.57%N.

EXAMPLE 101'-[4,4-Bis(4-fluorophenyl)-3-butenyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]maleate

The compound2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate (5 g, 15.5mmole) was converted to its free base and dried. The residue wasdissolved in 50 ml of DMF and stirred with 4.8 g of4,4-bis(4-fluorophenyl)-1-chloro-3-butene, 5 g of K₂ CO₃ (anhydrous,milled) and 25 mg of potassium iodide under nitrogen. The mixture wasquenched with water and extracted with ether. The ether extracts werecombined and washed with saturated brine. The ether was removed in vacuoand the residue was loaded onto a 100 g alumina column packed in ether.Fractions of 50 ml of ether were eluted and the desired material foundin maleate salt was precipitated. The material was washed with ether,filtered and vacuum dried, resulting in 2 g of1'-[4,4-bis-(4-fluorophenyl)-3-butenyl]-2-methylspiro[2H-1,4-benzodioxepin-3-(5H)4'-piperidine]maleate(3.38 mole, 21.81%). This material appeared pure by TLC on silica gel inchloroform:methanol (9:1), R_(f) =0.5 and in dichloromethane:2-propanol(1:1), R_(f) =0.8. MS (ci MH⁺ =476), NMR-CDCl₃ and IR-CHCl₃ areconsistent with the structure, m.p.=144°-149° C.(d).

ANALYSIS. Calculated for C₃₄ H₃₅ F₂ NO₆ : 69.01%C, 5.97%H, 2.37%N.Found: 68.67%C, 5.83%H, 2.44%N.

EXAMPLE 111'-(4,4-Diphenylbutyl)-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate

The compound2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride (5g, 18.55 mmole) was converted to its free base and dried. The oil wasdissolved in 50 ml of DMF and stirred under nitrogen with 15 mg ofpotassium iodide, 5 g of potassium carbonate (milled, anhydrous) and4.99 g of 4,4-diphenylbutylchloride (20.4 mmole) at ambient temperature,overnight. The reaction was determined to be complete by TLC. Themixture was quenched with water and extracted with ether. The solventwas removed in vacuo and the residue was loaded onto a 100 g aluminacolumn packed in ether. Fractions of 50 ml were eluted and the desiredmaterial was found in numbers 2-5, which were combined. The oxalate saltwas precipitated and recrystallized from 2-propanol/methanol. Theresultant product, 2.4 g of1'-[4,4-diphenylbutyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate(4.52 mmole, 24.3%), appeared pure by TLC on silica gel inchloroform:methanol (9:1), R_(f) =0.5 and in dichloromethane:2-propanol(1:1), R_(f) =0.4. MS (17 ev; M⁺ =441), NMR-DMSO-d₆ and IR-KBr areconsistent with the structure, m.p. 192°-194° C.

ANALYSIS. Calculated for C₃₂ H₃₇ NO₆ : 72.28%C, 7.03%H, 2.63%N. Found:72.06%C, 7.03%H, 2.42%N.

EXAMPLE 121'-[4,4-Diphenyl-3-butenyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]maleate

The compound2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride (5g, 18.6 mmole) was converted to its free base and dried. The resultantoil was dissolved in 50 ml of DMF and stirred with 5 g of potassiumcarbonate (milled, anhydrous), 15 mg of potassium iodide and 4.95 g of4,4-diphenyl-3-butenyl chloride (20.4 mmole) for 2 days at ambienttemperature under nitrogen. The reaction was determined to be completeby TLC and quenched with an equal volume of water. The products wereextracted with ether and the combined extracts reduced in volume invacuo. The remaining oil was loaded onto a 100 g alumina column packedin ether. Elution of 50 ml fractions resulted in the desired productsbeing found in numbers 2-4. These fractions were combined and themaleate salt was precipitated. The solids were recrystallized from2-propanol/methanol yielding 2.0 g of1'-[4,4-diphenyl-3-butenyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]maleate (3.6 mmole, 19.4%). Thismaterial appeared pure by TLC on silica gel in chloroform:methanol(9:1), R_(f) =0.6 and in dichloromethane:2-propanol (1:1), R_(f) =0.8.MS (ci MH⁺ =440), NMR-DMSO-d₆ and IR-KBr are consistent with thestructure, m.p. 170°-171° C.

ANALYSIS. Calculated for C₃₄ H₃₇ NO₆ : 73.48%C, 6.72%H, 2.52%N. Found:73.38%C, 6.70%H, 2.56%N.

EXAMPLE 132-Methyl-1'-[3,3-diphenylpropyl]spiro[2H-1,4-dibenzodioxepin-3(5H)4'-piperidine]oxolate

The compound2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride (5g, 18.6 mmole) was dissolved in 100 ml of DMF and stirred along with 5 gof potassium carbonate (milled, anhydrous), 15 mg of potassium iodideand 4.7 g of 3,3-diphenylpropylchloride (20.41 mmole). The mixture washeated to 90° C. for 3 hrs. under nitrogen after which the reaction wasdetermined to be complete by TLC. The reaction was quenched with waterand extracted with ether. The extracts were combined, reduced in volumeunder vacuum and loaded onto a 100 g alumina column packed in ether.Fractions of 50 ml were collected and the desired product was found innumbers 2-5. These fractions were combined, after which the oxalate saltwas precipitated. The solids were recrystallized from 2-propanolresulting in 2.6 g of2-methyl-1'-[3,3-diphenylpropyl]spiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate(6.6 mmole, 35.42%) which appeared pure on TLC in chloroform:methanol(9:1), R_(f) =0.6 and in dichloromethane:2-propanol (1:1), R_(f) =0.5,m.p.=178°-182° C. MS (ci MH⁺ =428), NMR-DMSO-d₆ and IR-KBr areconsistent with the structure.

ANALYSIS. Calculated for C₃₁ H₃₅ NO₆ : 71.92%C, 6.83%H, 2.70%N. Found:72.09%C, 6.78%H, 3.16%N.

EXAMPLE 141'-[4-(4-Fluorophenyl)butyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride

The compound2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride (5g, 18.6 mmole) was dissolved in 100 ml of DMF and stirred under nitrogenat 90° C. with 5 g of potassium carbonate (milled, anhydrous), 15 mg ofpotassium iodide, and 3.80 g of 4-(4-fluorophenyl)butyl chloride (20.4mmole) overnight. The reaction was determined to be complete by TLC. Themixture was cooled to ambient temperature, quenched with water andextracted into ether. The ether extracts were backwashed with saturatedbrine and the solvent was removed under vacuum. The residue was loadedonto a 100 g alumina column packed in ether and 50 ml fractions wereeluted. The desired material was found in fractions 2-4, which weresubsequently combined. The hydrochloride was precipitated andrecrystallized from methanol-water resulting in 2.4 g of1'-[4-(4-fluorophenyl)butyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]-hydrochloride(5.7 mmole, 30.78%) which appeared pure by TLC on silica gel inchloroform:methanol (9:1), R_(f) =0.8, and in dichloromethane:2-propanol(1:1), R_(f) =0.7. MS (MH⁺ =384), NMR-DMSO-d₆ and IR-KBr are consistentwith the structure, m.p.=212°-213° C.

ANALYSIS. Calculated for C₂₄ H₃₁ ClFNO₂ : 68.63%C, 7.45%H, 3.33%N.Found: 68.67%C, 7.49%H, 3.65%N.

EXAMPLE 151'-[4,4-Bis(4-chlorophenyl)butyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate

The compound2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride (4.0g, 15.0 mmole) was dissolved in 150 ml of DMF. To the solution was added4 g of potassium carbonate (milled, anhydrous), 15 mg of potassiumiodide, and 5.12 g of 4,4-bis(4-chlorophenyl)butylchloride (15.0 mmole).The reaction mixture was stirred at 80° C., under nitrogen, overnight.The reaction was determined to be complete by TLC. The mixture wasquenched with an equal volume of water and extracted with ether. Theether extracts were combined, backwashed with saturated brine and thesolvent was removed under vacuum. The residue was loaded onto a 100 galumina column packed into ether. Fractions of 50 ml were eluted and thedesired product was found in numbers 3-5. These fractions were combinedand the oxalate salt was precipitated. The solids were recrystallizedfrom tolueneethanol yielding 2.1 g of1'-[4,4-bis(4-chlorophenyl)butyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate (3.50 mmole, 23.3%). This material appearedpure by TLC on silica gel in chloroform:methanol (9:1), R_(f) =0.5 andin dichloromethane; 2-propanol (1:1), R_(f) =0.4. MS (ci MH⁺ =510) andin dichloro- and IR-KBr are consistent with the structure, m.p.192°-195° C.

ANALYSIS. Calculated for C₃₂ H₃₅ Cl₂ NO₆ : 63.99%C, 5.89%H, 2.33%N.Found: 63.68%C, 5.94%H, 2.25%N.

EXAMPLE 161'-[4,4'-Diphenyl-3-butenyl)-7-chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate

The compound7-chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride(5 g, 16.5 mmole), 5 g of potassium carbonate (milled, anhydrous), 15 mgof potassium iodide and 4.39 g of 4,4-diphenyl-3-butenylchloride (18.1mmole) were combined in 50 ml of DMF and stirred at 90° C. for 2 hrunder nitrogen. The reaction was determined to be conplete by TLC, afterwhich time it was quenched with water and extracted with ether. Theether extracts were combined and the solvent was removed under vacuum.The residue was loaded onto a 100 g alumina column packed in ether.Fractions of 50 ml of ether were collected and the desired material wasfound in numbers 2-4. Combination of these fractions was followed byprecipitation of the oxalate salt. The solids were recrystallized from2-propanol/methanol resulting in 2 g of1'-[4,4-diphenyl-3-butenyl]-7-chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate (3.6 mmole, 21.6%) which appeared pure by TLCon silica gel in chloroform:methanol (9:1), R_(f) =0.5 and indichloromethane:2-propanol (1:1), R_(f) =0.4. MS (ci MH⁺ =474),

NMR-DMSO-d₆ and IR-KBr are consistent with the structure, m.p.=214°-215°C.

ANALYSIS. Calculated for C₃₂ H₃₄ ClNO₆ : 68.13%C, 6.09%H, 2.48%N. Found:67.95%C, 6.05%H, 2.45%N.

EXAMPLE 171'-[4,4-Diphenylbutyl]-7-chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate

The compound7-chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride(5 g, 16.5 mmole), 5 g of potassium carbonate (milled, anhydrous), 15 mgof potassium iodide and 4.43 g of 4,4-diphenylbutyl chloride (18.1mmole) were combined in 50 ml of DMF. This mixture was stirred at 90° C.for 2 hr. under nitrogen. The reaction was determined to be complete byTLC, after which time it was quenched with water and extracted withether. The ether extracts were combined and the solvent was removedunder vacuum. The residue was loaded onto a 100 g alumina column packedin ether. Fractions of 50 ml were collected and the desired material wasfound in numbers 2-10. Combination of these fractions was followed byprecipitation of the oxalate salt. The solids were recrystallized from2-propanol-methanol resulting in 5.0 g of1'-[4,4-diphenylbutyl]-7-chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]-oxalate (8.8 mmole, 53.52%) which appeared pure by TLCon silica gel in chloroform:methanol (9:1), R_(f) =0.5 and indichloromethane:2-propanol (1:1), R_(f) =0.4. Mass Spec (MH⁺ =476),NMR=DMSO-d₆ and IR-KBr are consistent with the structure, m.p.=161°-165°C.

ANALYSIS. Calculated for C₃₂ H₃₆ ClNO₆ : 67.89%C, 6.42%H, 2.47%N. Found:67.64%C, 6.51%H, 2.36%N.

EXAMPLE 181'-[4,4-Bis(4-fluorophenyl)butyl]-7-chloro-2-methylspiro-[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate

The compound7-chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride(5 g, 16.5 mmole) was dissolved in 100 ml of DMF and was stirred with 5g of potassium carbonate (milled, anhydrous) for 1 hr. To the resultantmixture 15 mg of potassium iodide and 5.5 g of4,4-bis(4-fluorophenyl)butyl chloride (19.6 mmole) was added. Themixture was stirred under a nitrogen atmosphere at 90° C. for 6 hr. Thereaction was determined to be complete by GLC (OV 101; temperatureprogram: 225° C. (2 min) rate=30°/min to 280° C. (20 min) flow≅30ml/min). The reaction mixture was cooled to ambient temperature,quenched with water and extracted with ether. The ether extracts werebackwashed with saturated brine followed by removal of the solvent undervacuum. The residue was loaded onto a 100 g alumina column packed inether. Fractions of 50 ml of ether were collected and the desiredmaterial was found to be in numbers 2-5. These fractions were combinedand the oxalate salt of the product was precipitated. The white solidswere recrystallized from 2-propanol-methanol resulting in 5.3 g of1'-[4,4-bis(4-fluorophenyl)butyl]-7-chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate(8.8 mmole 53.50%) which appeared pure by TLC on silica gel inchloroform:methanol (9:1), R_(f) =0.5 and in dichloromethane:2-propanol(1:1), R_(f) =0.4. MS (MH⁺ =5.12),

NMR-CDCl₃ /DMSO-d₆ and IR-KBr are consistent with the structure,

m.p.=170°-174° C.

ANALYSIS. Calculated for C₃₂ H₃₄ ClF₂ NO₆ : 63.83%C, 5.70%H, 2.33%N.Found: 63.66%C, 5.58%H, 2.21%N.

EXAMPLE 191'-[4,4-Bis(4-fluorophenyl)-3-butenyl]-7-chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate

The compound7-chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride(5 g, 16.5 mmole) was dissolved in 100 ml of DMF and stirred with 5 g ofpotassium carbonate (milled, anhydrous) and 15 mg of potassium iodide.To the mixture was added 5 g of 4,4-bis(4-fluorophenyl)-3-butenylchloride (18.1 mmole), and the mixture was stirred at ambienttemperature overnight. TLC indicated that no reaction had occurred. Themixture was heated to 90° C. and after 3 hr products could be detected.Upon examination by GC/MS, it was determined that under these conditionsthe alkylating agent was not only reacting with the amine to form thedesired product, but was also decomposing. The temperature of thereaction mixture was lowered to 55° C. The reaction was driven tocompletion through the addition of excess4,4-bis(4-fluorophenyl)-3-butenyl chloride. Gas chromatographicconditions for the product were as follows: OV-101, 20 ml/min,temperature program, 225°-280° C., rate=30° C./min, t_(R) ≅12.5 min. Thereaction was quenched with an equal volume of water and the productswere extracted into ether. The extracts were combined, backwashed withsaturated brine and reduced in volume under vacuum. The residue wasloaded onto a 100 g alumina column packed in ether. Fractions of 50 mlwere collected and the desired material was in fraction numbers 3-6. Theappropriate fractions were combined and the oxalate salt precipitated.The solids were recrystallized from 2-propanol/methanol resulting in 2.3g of1'-[4,4-bis(4-fluorophenyl)-3-butenyl]-7-chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate(3.8 mmole, 23.2%), which appeared pure by TLC on silica gel inchloroform:methanol (9:1), R_(f) =0.6 and in dichloromethane:2-propanol,(1:1), R_(f) =0.5. MS (MH⁺ =510), NMR-TFA and IR-KBr are consistent withthe structure,

m.p.=212°-214° C.

ANALYSIS. Calculated for C₃₂ H₃₄ Cl₂ NO₆ : 64.04%C, 5.39%H, 2.33%N.Found: 64.00%C, 5.45%H, 2.32%N.

EXAMPLE 207-Chloro-2-methyl-1'-(3,3-diphenylpropyl)spiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride

The compound7-chloro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride(7.4 g, 24.3 mmole) was dissolved in 200 ml of DMF and stirred with 7.5g of milled, anhydrous potassium carbonate. 3,3-Diphenylpropyl chloride(6.2 g, 26.7 mmole) and 25 mg of potassium iodide were added to themixture which was heated at 90° C. under nitrogen overnight. Thereaction which was determined to be complete by TLC, was cooled andquenched with an equal volume of water. The products which wereextracted into ether, were backwashed with saturated brine. The etherwas removed under vacuum and the residue loaded onto a 200 g aluminacolumn packed in ether. Fractions of 75 ml were collected and thedesired material was found in numbers 4-7. These fractions were combinedand the hydrochloride salt was precipitated. The material wasrecrystallized from toluene-ethylacetate resulting in 2 g of7-chloro-2-methyl-1'-(3,3-diphenylpropyl)spiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride(4.0 mmole, 16.5%) which appeared pure by TLC on silica gel inchloroform:methanol (9:1), R_(f) =0.6 and in dichloromethane:2-propanol(1:1), R_(f) =0.5. A second crop (2.7 g, 5.2 mmole, 22.3%) was obtainedhaving equal purity, MS (MH⁺ =261), NMR-CDCl₃ and IR-CHCl₃ areconsistent with the structure, m.p=224°-225° C.,

ANALYSIS. Calculated for C₂₉ H₃₃ Cl₂ NO₂ : 69.86%C, 6.69%H, 2.81%H.Found: 69.98%C, 6.60%H, 2.72%N.

EXAMPLE 217-Bromo-1'-[4,4-bis(4-fluorophenyl)butyl]-2-methylspiro-[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate

The compound7-bromo-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride(7.0 g, 20.1 mmole) was dissolved in 150 ml of DMF. The solution wasstirred with 7.0 g of potassium carbonate (milled, anhydrous), 15 mg ofpotassium iodide and 6.2 g of 4,4-bis(4-fluorophenyl)butyl chloride(22.1 mmole) at 80° C. under nitrogen overnight. The reaction, which wasdetermined to be complete by TLC, was cooled to ambient temperature,quenched with an equal volume of water, and extracted with ether. Theether extracts were combined and backwashed with saturated brine. Theether was removed under vacuum and the oily residue loaded onto a 140 galumina colum packed in ether. Fractions of 50 ml were collected and thedesired material was found in numbers 2-4. These fractions were combinedand the oxalate salt precipitated. The solids, which were recrystallizedfrom ethyl acetate/methanol, appeared to be pure7-bromo-1'-[4,4-bis(4-fluorophenyl)butyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]-oxalate (4.30 g, 6.7 mmole, 33.1%)by TLC on silica gel in chloroform:methanol (9:1), R_(f) =0.5 and indichloromethane:2-propanol (1:1), R_(f) =0.4, MS (MH⁺ =556/558),NMR-DMSO-d₆ and IR-KBr are consistent with the structure, m.p.=183°-186°C.

ANALYSIS. Calculated for C₃₂ H₃₄ BrF₂ NO₆ : 59.44%C, 5.31%H, 2.17%N.Found: 59.25%C, 5.26%H, 2.19%N.

EXAMPLE 221'-[4-(4-Fluorophenyl)-4-oxobutyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate

The compound2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride (50g, 185.5 mmole) was dissolved in 1.5 l of DMF and stirred under nitrogenwith 50 g of milled, anhydrous potassium carbonate for 4 hr. To thismixture was added 50.3 g of γ-chloro-p-fluorobutyrophenone dimethylketal (204.1 mmole) and 0.15 g of potassium iodide. The resultantmixture was heated to 90° C. and allowed to react overnight, after whichtime the reaction was determined to be complete by TLC. The mixture waspoured into water and the product extracted into ether. The etherextracts were combined, backwashed with saturated brine and reduced involume under vacuum. The residue was dissolved in 800 ml of methanol and300 ml of 3N hydrochloric acid. The mixture was heated to reflux undernitrogen and stirred for 2 hr. The solution was cooled and reduced involume under vacuum. The residue was suspended in saturated aqueoussodium carbonate and extracted into ether. The extracts were combined,backwashed with saturated brine and dried over anhydrous potassiumcarbonate The ether was removed under vacuum from the extract and theresidue loaded onto a 1000 g alumina column packed in ether. Fractionsof 500 ml of ether were collected and the desired product was found innumbers 2-4, which were combined. The oxalate salt was precipitated andrecrystallized from 2-propanol, resulting in 28.6 g of1'-[4-(4-fluorophenyl)-4-oxobutyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate(58.7 mmole, 31.6%) which appeared pure by TLC on silica gel inchloroform:methanol (9:1), R_(f) =0.5 and dichloromethane:2-propanol(1:1), R_(f) =0.4, m.p.=134°-137° C. MS (MH⁺ =488), NMR-DMSO-d₆ andIR-KBr are consistent with the structure.

ANALYSIS. Calculated for C₂₆ H₃₀ FNO₇ : 64.05%C, 6.21%H, 2.87%N. Found63.72%C, 6.15%H, 2.90%N.

EXAMPLE 231'-[4-Hydroxy-4-(4-fluorophenyl)butyl]-2-methylspiro-[2H-1,4-benzodioxepin-3(5H)4'-piperidine]

The compound1'-[4-(4-fluorophenyl)-4-oxobutyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate(15 g, 30.8 mmole) was converted to its free base and dried. The residuewas dissolved in 50 ml of ethanol and stirred with 0.8 g of sodiumborohydride (pellets) under a nitrogen atmosphere, over the weekend, atambient temperature. The mixture was stirred with 40 ml of 3N HCl whichresulted in the formation of solids. The solids were insoluble in waterand could be recrystallized from ethyl acetate (8.7 g, 20.0 mmole,65.0%). Upon treatment with saturated sodium carbonate solution andchloroform, all solids were dissolved. After drying the organic phase,and the removal of the solvent, there remained a crystalline solid whichcould be recrystallized from chloroform/hexane. The material wasidentified as1'-[4-hydroxy-4-(4-fluorophenyl)butyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine].The compound appeared pure by TLC on silica gel in chloroform:methanol(9:1), R_(f) =0.5, and in dichloromethane:2-propanol, (1:1), R_(f) =0.4.MS (MH⁺ =400), NMR-CDCl₃ and IR-CHCl₃ are consistent with the structure,m.p.=143°-146° C.

ANALYSIS. Calculated for C₂₄ H₃₀ FNO₃ : 72.14%C, 7.58%H, 3.50%N. Found:72.00%C, 4.49%H, 3.38%N.

EXAMPLE 241'-[4-(4-Fluorophenoxy)-4-(4-fluorophenyl)butyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate

Sodium hydride (0.96 g of a 50% mineral oil suspension, 0.02 mole) washexane washed, suspended in 80 ml of DMSO and heated to 60°-70° C. untilevolution of hydrogen ceased. The mixture was cooled to 5° C. and to itwas added a solution of 6.8 g of1'-[4-hydroxy-4-(4-fluorophenyl)butyl]-2-methyl-spiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]dissolved in 225 ml of DMSO The mixture was stirred at ambienttemperature for 15 min. after which 8.0 g of 1,4-difluorobenzene (0.07mole) was added. The mixture was heated to 70° C. and maintained at thattemperature overnight. TLC indicated 50-60% completion of reaction whichwas not improved by heating at 80° C. The mixture was cooled to ambienttemperature and quenched with an equal volume of water. The productswere extracted into ether and backwashed with saturated brine. The etherwas removed under vacuum and the residue purified by preparative HPLCusing two silica gel columns (2×500 cc) eluting withhexane:ether:methanol (10:10:1). The desired material was detected byrefractive index and ultraviolet absorption. The fractions whichcontained the product were combined and the solvent removed undervacuum. The oil residue was dissolved in ether and the oxalate saltprecipitated. The solids were recrystallized from ethylacetate:methanol.The resultant1'-[4-(4-fluorophenoxy)-4-(4-fluorophenyl)butyl]-2-methylspiro-[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate(3.9 g, 7.9 mmole 39.5%) appeared pure by TLC on silica gel inchloroform:methanol (9:1), R_(f) =0.5 and in hexane:ether:methanol(10:10:1). R_(f) =0.3. MS (MH⁺ =494), NMR-DMSO-d₆, CMR-DMSO-d₆ andIR-KBr are consistent with the structure, m.p.=180°-182° C.

ANALYSIS. Calculated for C₃₂ H₃₅ F₂ NO₃ : 65.85%C, 6.06%H, 2.40%N.Found: 66.05%C, 6.07%H, 2.27%N.

EXAMPLE 25 1-Acetyl-4-ethynyl-4-(2,5-difluorophenylmethoxy)piperidine

A solution of 7.0 g of potassium t-butoxide (62.5 mmole) in 20 ml of dryDMF was added dropwise to a chilled solution of 10 g of1-acetyl-4-ethynyl-4-hydroxypiperidine (59.9 mmole) in 75 ml of dry DMF,at such a rate as to maintain the temperature at 10° C. The mixture wasallowed to equilibrate at 10° C. for 15 min. after which time it wascooled to -20° C. 2,5-Difluorobenzyl chloride (9.73 g, 59.9 mmole) wasadded dropwise at a rate such as to maintain the reaction temperature atabout -20° C. After complete addition the reaction mixture was warmed to0° C. and allowed to react for 1 hr. The reaction appeared to becomplete by GLC and was quenched with ice and water. The products wereextracted into ether and dried over K₂ CO₃. After filtration the solventwas removed under vacuum. The crystalline product was recrystallizedfrom cyclohexane and dried, affording 10.5 g of1-acetyl-4-ethynyl-4-(2,5-difluorophenylmethoxy)piperidine (35.8 mmole,59.83%). This material appeared pure by GLC (99% on OV225, temperatureprogram: 200° C. (2 min.), rate=25° C./min., 250° C. (15 min.), flow=30ml/min. t_(R) =4.00 min.) and by TLC on silica gel inhexane:ethylacetate (1:1), R_(f) =0.2. Mass Spec (ci MH⁺ =294),

NMR-CDCl₃ and IR-CHCl₃ are consistent with the structure,

m.p.=90°-93° C.

ANALYSIS. Calculated for C₁₆ H₁₇ F₂ NO₂ : 65.51%C, 5.85%H, 4.77%N.Found: 65.72%C, 5.87%H, 4.68%N.

EXAMPLE 26 4-(1-Oxoethyl)-4-(2,5-difluorophenylmethoxy)piperidinehydrochloride

The compound 1-acetyl-4-ethynyl-4-(2,5-difluorophenylmethoxy)piperidine(5 g, 17.1 mmole) was suspended in 50 ml of 15% sulfuric acid. Themixture was heated at reflux under nitrogen for 1 hr. after whichcomplete dissolution occurred. Mercuric sulfate (0.25 g, freshly opened)was added to the cooled solution. The mixture was heated at 65° C.overnight. The reaction was determined to be 98% complete by GLC. Themixture was basified with saturated aqueous sodium carbonate andextracted with chloroform. The organic extracts were combined, driedover K₂ CO₃ and filtered through celite. The filtrate was reduced involume under vacuum and the residue dissolved in ether. Thehydrochloride salt was precipitated and recrystallized fromethylacetate/ethanol, yielding, in two crops, 3.2 g of4-(1-oxoethyl)-4-(2,5-difluorophenylmethoxy)piperidine hydrochloride(10.48 mmole, 61.4%) which appeared pure by GLC (OV225, temperatureprogram 200° C. (2 min.), rate=25°/min., 250° C. (15 min.), flow= 30ml/min., t_(R) =1.59) and by TLC on silica gel in 2-propanol:ammoniumhydroxide (8:2), R_(f) =0.8, MS (ci MH⁺ =270), NMR-DMSO-d₆ and IR-KBrare consistent with the structure, m.p.=197°-201° C.

ANALYSIS. Calculated for C₁₄ H₁₈ ClF₂ NO₂ : 54.99%C, 5.95%H, 4.58%N.Found: 55.03%, 5.88%H, 4.70%N.

EXAMPLE 27 4-(1-Hydroxyethyl)-4-(2,5-difluorophenylmethoxy)piperidine

The compound 4-(1-oxoethyl)-4-(2,5-difluorophenylmethoxy)piperidinehydrochloride (5 g, 16.4 mmole) was dissolved in 50 ml of water. The pHwas adjusted to 8.5 using 50% sodium hydroxide. Sodium borohydride (0.2g, 4.5 mmole) was added to the solution and the mixture was allowed toreact for 1/2 hr. The reaction was determined to be complete by GLC. Thereaction mixture was saturated with potassium carbonate and extractedwith ether. The ether extracts were combined, dried, and filtered. Thesolvent was removed under vacuum resulting in 4 g of solid whitematerial. This solid was recrystallized from cyclohexane resulting in3.5 g of 4-(1-hydroxyethyl)-4-(2,5-difluorophenylmethoxy)piperidine(12.9 mmole, 78.7%) which appeared pure by GLC (OV 225, temperatureprogram: 200° C. (2 min.), rate=25°/min., 250° C. (15 min.), flow=30ml/min., t_(R) =2.31) and by TLC on silica gel in 2-propanol:ammoniumhydroxide (8:2), R_(f) =0.5. MS (ci MH⁺ =272). NMR-CDCl₃ and IR-CHCl₃are consistent with the structure. m.p.=94°-96° C.

ANALYSIS. Calculated for C₁₄ H₁₉ F₂ NO₂ : 61.97%C, 7.07%H, 5.16%N.Found: 61.92%C, 7.26%H, 5.00%N.

EXAMPLE 28 7-Fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride

The compound 4-(1-hydroxyethyl)-4-(2,5-difluorophenylmethoxy)piperidine(84.4 g, 311.0 mmole) was dissolved in 510 ml of dry THF and stirredwith 36.6 g of potassium tert-butoxide (326.0 mmole). The mixture washeated at reflux under nitrogen for 8 hrs. after which a 10% excess ofpotassium tert-butoxide was added. The mixture was treated 6 hrs. afterwhich the reaction was determined to be complete by GLC. The mixture wascooled and quenched with saturated aqueous sodium carbonate. The productwas extracted into ether and dried over potassium carbonate. The driedether extracts were filtered and the hydrochloride salt wasprecipitated. The solids were filtered, dried (85.0 g, 287.0 mmole,92.9%), and recrystallized from ethylacetate/ethanol. The resultantcrystals were filtered and vacuum dried at 60° C. resulting in 62.6 g of7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride(218.0 mmole, 70.01%). The material appeared pure by GLC (OV225, flow=30ml/min., temperature program: 200° C. (2 min.), rate=25° C./min., silicagel in 2-propanol:ammoniumhydride (8:2), R_(f) =0.5. MS (ci MH⁺ =251),NMR-DMSO-d₆ and IR-KBr are consistent with the structure, m.p.=273°-277°Cd.

ANALYSIS. Calculated for C₁₄ H₁₉ ClFNO₂ : 58.43%C, 6.67%H, 4.86%N.Found: 58.30%C, 6.54%H, 4.80%N.

EXAMPLE 29 1'-(4,4-Diphenylbutyl)-7-fluoro-2-methylspiro-[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride

7-Fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride (5 g, 17.4mmole) was dissolved in 100 ml of DMF and stirred with 5 g of milled,anhydrous potassium carbonate, 15 mg of potassium iodide and 4.7 g of4,4-diphenylbutylchloride (19.1 mmole) at 65° C. under nitrogenovernight. The reaction which was determined to be complete by TLC wascooled, quenched with an equal volume of water and extracted with ether.The ether extracts were combined and backwashed with saturated sodiumchloride. The solvent was removed under vacuum. The oily residue wasloaded onto a 100 g alumina column packed with ether. Fractions of 50 mlwere collected and the desired material was found in numbers 2-3. Thesefractions were combined and the solvent was removed under vacuum. Theresidual oil was dissolved in anhydrous ether and the hydrochloride saltprecipitated. Recrystallization from toluene/ethyl acetate/ethanolafforded 3.0 g (6.1 mmole, 34.8%) of 1'-(4,4-diphenylbutyl)-7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride whichappeared pure by TLC on silica gel in dichloromethane:methanol (9:1),R_(f) =0.6 and in dichloromethane: 2-propanol (1:1), R_(f) =0.5. MS (ciMH⁺ =460). NMR-DMSO-d₆ and IR-KBr are consistent with the structure.m.p.=215°-218° C.

ANALYSIS. Calculated for C₃₀ H₃₅ ClFNO₂ : 72.63%C, 7.13%H, 2.82%N.Found: 72.73%C, 6.74%H, 2.56%N.

EXAMPLE 301'-[4,4-Bis-(4-fluorophenyl)butyl]-7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride

7-Fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride(5.0 g, 17.4 mmole) was dissolved in 100 ml of DMF and stirred with 5 gof milled, anhydrous potassium carbonate, 15 mg potassium iodide and 5.4g of 4,4-bis(4-fluorophenyl)butylchloride (19.1 mmole) at 65° C. undernitrogen overnight. The reaction which was determined to be complete byTLC, was cooled, quenched with an equal volume of water and extractedwith ether. The ether extracts were combined and back-washed withsaturated brine. The solvent was removed under vacuum. The oily residuewas loaded onto a 100 g alumina column packed in ether. Fractions of 50ml were collected and the desired product was found in numbers 2-4.These fractions were combined and the solvent was removed under vacuum.The residual oil was dissolved in anhydrous ether and the hydrochloridesalt precipitated. Recrystallization from toluene ethyl acetate/ethanolafforded 5.9 g (7.3 mmole, 42.2%) of 1'-[4,4-bis(4-fluorophenyl)butyl]-7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloridewhich appeared pure by TLC on silica gel in dichloromethane:methanol(9:1), R_(f) =0.6 and in dichloromethane:2-propanol (1:1), R_(f) =0.5.MS (ci MH⁺ =496), NMR-DMSO-d₆ and IR-KBr are consistent with thestructure, m.p.=162°-165° C.

ANALYSIS. Calculated for C₃₀ H₃₃ ClF₃ NO₂ : 67.72%C, 6.26%H, 2.63%N.Found: 67.35%C, 5.95%H, 2.56%N.

In Examples 31 to 36, an alternate method for preparing the compound offormula (7) in FIG. 1 is described. The1-methyl-4-ethynyl-4-hydroxypiperidine employed as starting material inExample 31 can be prepared by the method disclosed in N. Barbulescu, C.Bornaz and C. Greff, Rev. Chim. (Bucharest) 20 (6): 373-374 (1969).

EXAMPLE 31 1-Methyl-4-ethynyl-4-(2-fluorophenylmethoxy)piperidineoxalate

To a stirred suspension of 7.8 g of NaH (163.0 mmole), 50% in oil;washed three times with hexane) in 80 ml dry DMF was added dropwise asolution of 20 g (144.0 mmole) of 1-methyl-4-ethynyl-4-hydroxypiperidine in 120 ml of DMF. The solution was allowed to cool to roomtemperature and, subsequently, 20 ml (169.0 mmole) of 2-fluorobenzylchloride was added dropwise. The mixture was allowed to stir overnight,poured slowly into water, extracted twice with ether, washed withsaturated sodium chloride, dried over potassium carbonate, filtered andthe solvent evaporated, yielding1-methyl-4-ethynyl-4-(2-fluorophenylmethoxy)piperidine oxalate (35.2 g104.0 mmole, 72.0%).

ANALYSIS. Calculated for C₁₅ H₁₈ FNO.C₂ H₂ O₄ : 60.70%C, 6.01%H, 4.16%N.Found: 60.42%C, 5.97%H, 4.08%N.

EXAMPLE 32 4-(1-Oxoethyl)-4-(2-fluorophenylmethoxy)-1-methylpiperidineoxalate

To a suspension of 1-methyl-4-(2-fluorophenylmethoxy)-piperidine(liberated from 30.6 g, 90.7 mmole, of the oxulate, and 165 ml of waterwas added a solution of 22 ml of conc. sulfuric acid in 53 ml of water.To the solution was added 4.0 g (13.4 mmole) of mercuric sulfate. Themixture was heated at reflux for 1.5 hr. under nitrogen and allowed tocool to room temperature. The mixture was poured into cold saturatedsodium carbonate, extracted twice with ether and washed with saturatedsodium chloride. The ether solution was dried over anhydrous potassiumcarbonate, filtered and the solvent evaporated to provide an oil. Theoxalate salt was precipitated, and recrystallization frommethanol/ethanol provided 21.1 g (59.4%) of4-(1-oxoethyl)-4-(2-fluorophenylmethoxy)-1-methyl piperidine oxalate.The material appeared pure by TLC on silica gel in methanol:methylenechloride (9:1), R_(f) =0.4 and on alumina in ether, R_(f) =0.3. IR(Nujol), NMR-DMSO-d₆ and MS (ci MH⁺ =266) are consistent with thestructure, m.p.=180°-181° C.

ANALYSIS. Calculated for C₁₅ H₂₀ FNO₂.C₂ H₂ O₄ : 57.45%C, 6.24%H,3.94%N. Found: 57.25%C, 6.26%H, 3.82%N.

EXAMPLE 334-(1-Hydroxyethyl)-4-(2-fluorophenylmethoxy)-1-methylpiperidine oxalate

Sodium borohydride (533 g, 1.4 mole) was dissolved in 4500 ml methanol.To the resulting solution was added, with stirring, a solution of4-(1-oxoethyl)-4-(2-fluorophenylmethoxy)-1-methylpiperidine (151 g, 0.6mole) in 500 ml methanol. The reaction was allowed to proceed at 0° C.for 1.5 hrs. The reaction mixture was made basic with 3 l. of saturatedaqueous Na₂ CO₃ causing a precipitate to form. To the mixture was added2 l. diethyl ether. The resulting solution was worked up with cold waterand diethyl ether and the diethyl ether extracts were combined. Theoxalate salt was precipitated and recrystallized from 2-propanol. Afterrecrystallization, filtration and drying in vacuo at 45° C., 32 g of4-(1-hydroxyethyl)-4-(2-fluorophenylmethoxy)-1-methylpiperidine oxalatewere obtained. MS (ci MH⁺ =268), NMR-DMSOd₆ and IR-KBr were consistentwith the structure, m.p.=104°-106° C.

ANALYSIS. Calculated for C₁₄ H₂₄ NO₆ F: 57.12%C, 6.78%H, 3.92%N. Found:56.65%C, 6.72%H, 3.77%N.

EXAMPLE 341',2-dimethylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate

The free base of4-(1-hydroxyethyl)-4-(2-fluorophenylmethoxy)-1-methylpiperidine wasgenerated from its oxalate with saturated sodium bicarbonate andextracted into chloroform. This was dried over anhydrous sodium sulfate,taken to dryness, weighed (30.3 g, 115.0 mmole) and dissolved in 300 mlof dry dimethylformamide. This solution was added dropwise and undernitrogen to a stirred suspension of hexane washed sodium hydride (6.5 g50% mineral oil suspension, 136.0 mmole). The mixture was heated to 130°C. and stirred for 0.5 hr. The reaction was quenched, when conversionwas greater than 90% by GLC (3% ASI column, flow=45 ml/min, 200° C.), byadding ice and water. The products were isolated by ether extraction.The extracts were dried over anhydrous potassium carbonate, filtered andthe oxalate salt precipitated. Recrystallization was carried out inmethanol resulting in 11.1 g of1',2-dimethylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]oxalate. Thematerial appeared pure by thin layer chromatography on silica gel inchloroform:methanol (1:1), R_(f) =0.25 and on alumina inchloroform:methanol (95:5), R_(f) =0.90. MS (ci MH⁺ =248).

IR:KBr and NMR-DMSO-d₆ are consistent with the structure.

m.p.=162°-165° C.

ANALYSIS. Calculated for C₁₅ H₂₁ N₁ O₂.C₂ H₂ O₄ : 60.53%C, 6.82%H,4.15%N. Found: 60.26%C, 6.85%H, 4.10%N.

EXAMPLE 351'-(Phenoxycarbonyl)-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]

The compound 1',2-dimethylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine](194.4 g, 787.0 mmole) was dissolved with stirring under a nitrogenblanket in 2 l, of dichloromethane. Anhydrous K₂ CO₃ (131 g) was addedto the resulting solution. Phenoxycarbonyl chloride (147.1 g, 930.0mmole) was then added with stirring. The resulting mixture was allowedto react overnight at ambient temperature. After successive acidic andalkaline washes, the mixture was dried over MgSO₄, filtered and taken todryness. A 10 g sample of the product was loaded onto a column of silicagel (100 g) packed in chloroform, and thirteen 75 ml fractions wererecovered. Mass spectra showed the compound to be in fractions 5-11.These fractions were combined and taken to dryness. The oily residue wascrystallized from hexane-cyclohexane resulting in 1.55 g of1'-phenoxycarbonyl-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]which appeared pure by TLC in chloroform:methanol (95:5 ) R_(f) =0.4. MS(ci MH⁺ =354), NMR-CDCl₃ and IR-CHCl₃ are consistent with the structure,m.p.=85°-89° C.

ANALYSIS. Calculated for C₂₁ H₂₃ NO₄ 71.36%C, 6.57%H, 3.96%N. Found:71.31%C, 6.60%H, 3.96%N.

EXAMPLE 362-Methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]-oxalate

1'-Phenoxycarbonyl-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine](44.0 g, 130.0 mmole) was dissolved in 230 ml methanol, to which wasadded 128.2 ml of 15% aqueous sodium hydroxide. With stirring undernitrogen, the mixture was heated to 60° C. and maintained at thattemperature for 18 hrs. The mixture was cooled to room temperature andextracted with chloroform. The chloroform extracts were combined anddried over anhydrous potassium carbonate, filtered and taken to dryness.The residue was dissolved in ethanol-ether (1:1) and the oxalate saltprecipitated (11.9 g, 0.037 mole, 28.31%). A 5 g sample wasrecrystallized from ethanol yielding 2.5 g of material which appearedpure by thin layer chromatography on silica gel in chloroform:methanol(1:1), R_(f) =0.1 and ethanol:ammonium hydroxide (7:3), R_(f) =0.85. MS(ci MH⁺ =234).

IR-KBr and NMR-DMSO-d₆ were all consistent with the structure.

m.p.=216°-218° C.

ANALYSIS. Calculated for C₁₅ H₂₁ N₁ O₂.C₂ H₂ O₄ : 60.53%C, 6.82%H,4.15%N. Found: 60.26%C, 6.85%H, 4.10%N.

EXAMPLE 37 1-Acetyl-4-ethynyl-4-(2,5-difluorophenylmethoxy)piperidine

A solution of 7.04 g of potassium t-butoxide (62.9 mmole) in 20 ml ofdry DMF was added dropwise to a chilled solution of 10 g of1-acetyl-4-ethynyl-4-hydroxypiperidine (59.9 mmole) in 75 ml of dry DMF,at such a rate as to maintain the temperature at 10° C. The mixture wasallowed to equilibrate at 10° C. for 15 min. after which time it wascooled to -20° C. To this solution was added 9.73 g of2,5-difluorobenzylchloride (59.9 mmole) at such a rate as to maintainthe temperature around -20° C. After complete addition, the reactionmixture was warmed to 0° C. and allowed to react for 1 hr. The reactionappeared to be complete by GLC and was quenched with ice and water. Theproducts were extracted into ether and dried over K₂ CO₃. Afterfiltration, the solvent was removed under vacuum. The crystallineproduct was recrystallized from cyclohexane and dried, affording 10.5 gof 1-acetyl-4-ethynyl-4-(2,5-difluorophenylmethoxy)piperidine (35.8mmole, 59.83%). This material appeared pure by GLC (99% on OV225,temperature program: 200° C. (2 min), rate=25° C./min, 250° C. (15 min),flow=30 ml/min t_(R) =4.00 min) and by TLC on silica gel inhexane:ethylacetate (1:1), R_(f) =0.2. MS (ci MH⁺ =294).

NMR-CDCl₃ and IR=CHCl₃ were consistent with the structure; m.p.=90°-93°C.

ANALYSIS. Calculated for C₁₆ H₁₇ F₂ NO₂ : 65.51%C, 5.85%H, 4.77%N.Found: 65.72%C, 5.87%H, 4.68%N.

EXAMPLE 38 4-(1-Oxoethyl)-4-(2,5-difluorophenylmethoxy)piperidinehydrochloride

The compound 1-acetyl-4-ethynyl-4-(2,5-difluorophenylmethoxy)piperidine(5 g, 17.06 mmole) was suspended in 50 ml of 15% sulfuric acid. Themixture was heated at reflux under nitrogen for 1 hr. after whichcomplete dissolution occurred. Mercuric sulfate (0.25 g. freshly opened)was added to the cooled solution. The mixture was heated at 65° C.overnight. The reaction was determined to be 98% complete by GLC. Themixture was basified with saturated aqueous sodium carbonate andextracted with chloroform. The organic extracts were combined, driedover K₂ CO₃ and filtered through celite. The filtrate was reduced involume under vacuum and the residue dissolved in ether. Thehydrochloride salt was precipitated and recrystallized fromethylacetate/ethanol, yielding, in two crops, 3.2 g of4-(1-oxoethyl)-4-(2,5-difluorophenylmethoxy)piperidine hydrochloride(10.48 mmole, 61.4%), which appeared pure by GLC (OV225, temperatureprogram 200° C. (2 min), rate=25°/min. 250° C. (15 min), flow= 30ml/min, t_(R) =1.59) and by TLC on silica gel in 2-propanol: ammoniumhydroxide (8:2), R_(f) =0.8. MS (ci MH⁺ =270), NMR-DMSO-d₆ and IR-KBrwere consistent with the structure; m.p.=197°-201° C.

ANALYSIS. Calculated for C₁₄ H₁₈ ClF₂ NO₂ : 54.99%C, 5.95%H, 4.58%N.Found: 55.03%C, 5.88%H, 4.70%N.

EXAMPLE 39 4-(1-Hydroxyethyl)-4-(2,5-difluorophenylmethoxy)piperidine

The compound 4-(1-oxoethyl)-4-(2,5-difluorophenylmethoxy)piperidinehydrochloride (5 g, 16.4 mmole) was dissolved in 50 ml of water. The pHwas adjusted to 8.5 using 50% sodium hyroxide. Sodium borohydride (0.2g, 4.5 mmole) was added to the solution and the mixture was allowed toreact for 1/2 hour. The reaction was determined to be complete by GLC.The reaction mixture was saturated with potassium carbonate andextracted with ether. The ether extracts were combined, dried andfiltered. The solvent was removed under vacuum resulting in 4 g of solidwhite material. This solid was recrystallized from cyclohexane resultingin 3.5 g of 4-(1-hydroxyethyl)-4-(2,5-difluorophenylmethoxy)piperidine(12.9 mmole, 78.7%), which appeared pure by GLC (OV225, temperatureprogram: 200° C. (2 min) rate=25°/min 250° C. (15 min) flow=30 ml/mint_(R) =2.31) and by TLC on silica gel in 2-propanol:ammonium hydroxide(8:2) R_(f) =0.5. MS (ci MH⁺ =272)

NMR-CDCl₃ and IR-CHCl₃ were consistent with the structure:

m.p.=94°-96° C.

ANALYSIS. Calculated for C₁₄ H₁₉ F₂ NO₂ : 61.97%C, 7.07%H, 5.16%N.Found: 61.92%C, 7.26%H, 5.00%N.

EXAMPLE 407-Fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride

The compound 4-(1-hydroxyethyl)-4-(2,5-difluorophenylmethoxy)piperidine(84.4 g. 0.311 mole) was dissolved in 510 ml of dry THF and stirred with36.6 g of potassium tert-butoxide (0.326 mole). The mixture was heatedat reflux under nitrogen for 8 hr after which a 10% excess of potassiumtert-butoxide was added. The mixture was heated 6 hr after which thereaction was determined to be complete by GLC. The mixture was cooledand quenched with saturated aqueous sodium carbonate. The product wasextracted into ether and dried over potassium carbonate. The dried etherextracts were filtered and the hydrochloride salt was precipitated. Thesolids were filtered, dried (83.0 g, 0.289 mole, 92.83%) andrecrystallized from ethyl acetate/ethanol. The resultant crystals werefiltered and vacuum dried at 60° C. resulting in 62.6 g of7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride(0.218 mole 70.01%). This material appeared pure by GLC (OV225, flow= 30ml/min, temperature program: 200° C. (2 min), rate=25° C. (15 min),t_(R) =1.82) and TLC on silica gel in 2-propanol:ammonium hydroxide(8:2), R_(f) =0.5. MS (ci MH⁺ =251), NMR-DMSO-d₆, and IR-KBr wereconsistent with the structure; m.p.=273°-277° C.(d).

ANALYSIS. Calculated for C₁₄ H₁₉ ClFNO₂ : 58.43%C, 6.67%H, 4.86%N.Found: 58.30%C, 6.54%H, 4.80%N.

EXAMPLE 411'-(4,4-Diphenylbutyl)-7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride

The compound7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride(5 g, 17.39 mmole) was dissolved in 100 ml of DMF and stirred with 5 gof milled, anhydrous potassium carbonate, 15 mg potassium iodide and 4.7g of 4,4-diphenylbutylchloride (19.13 mmole) at 65° C. under nitrogenovernight. The reaction, which was determined to be complete by TLC, wascooled. quenched with an equal volume of water and extracted with ether.The ether extracts were combined and backwashed with saturated sodiumchloride. The solvent was removed under vacuum. The oily residue wasloaded onto a 100 g alumina column packed in ether. Fractions of 50 mlwere collected and the desired material was found in fraction numbers2-3. These fractions were combined and the solvent was removed undervacuum. The residual oil was dissolved in anhydrous ether and thehydrochloride salt precipitated. Recrystallization from toluene/ethylacetate/ethanol afforded 3.0 g (6.05 mmole, 34.79%) of1'-(4,4-diphenylbutyl)-7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride,which appeared pure by TLC on silica gel in dichloromethane/methanol(9:1), R_(f) =0.6 and in dichloromethane/2-propanol (1:1), R_(f) =0.5.MS (ci MH⁺ =460), NMR-DMSO-d₆ and

IR-KBr were consistent with the structure; m.p.=215°-218° C.

ANALYSIS. Calculated for C₃₀ H₃₅ ClFNO₂ : 72.63%C, 7.13%H, 2.82%N.Found: 72.73%C, 6.74%H, 2.56%N.

EXAMPLE 421'-[4,4-Bis(4-fluorophenyl)butyl]-7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride

The compound7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride(5.0 g, 17.39 mmole) was dissolved in 100 ml of DMF and stirred with 5 gof milled, anhydrous potassium carbonate, 15 mg of potassium iodide and5.36 g of 4,4-bis(4-fluorophenyl)butylchloride at 65° C. under nitrogenovernight. The reaction, which was determined to be complete by TLC, wascooled, quenched with an equal volume of water and extracted with ether.The ether extracts were combined and backwashed with saturated brine.The solvent was removed under vacuum. The oily residue was loaded onto a100 g alumina column packed in ether. Fractions of 50 ml were collectedand the desired product was found in fraction numbers 2-4. Thesefractions were combined and the solvent was removed under vacuum. Theresidual oil was dissolved in anhydrous ether and the hydrochloride saltprecipitated. Recrystallization from toluene/ethyl acetate/ethanolafforded 3.9 g 0.34 mole, 42.21%) of1'[4,4-bis(4-fluorophenyl)butyl]-7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride,which appeared pure by TLC on silica gel in dichloromethane:methanol(9:1), R_(f) =0.6 and in dichloromethane:2-propanol (1:1), R_(f) =0.5.MS (ci MH⁺ =496), NMR-DMSO-d₆ and IR-KBr were consistent with thestructure; m.p.=162°-165° C.

ANALYSIS. Calculated for C₃₀ H₃₃ ClF₃ NO₂ : 67.72%C, 6.26%H, 2.63%N.Found: 67.35%C, 5.95%H, 2.56%N.

EXAMPLE 431'-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride

The compound7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride(5 g, 17.4 mmole) was suspended in 100 ml of n-butylacetate along with 5g of potassium carbonate (milled, anhydrous), 5.4 g of[2-[bis(4-fluorophenyl)methoxy]ethyl chloride (19.1 mmole) and 15 mg ofpotassium iodide. The mixture was stirred under nitrogen at refluxovernight. The reaction was determined to be complete by TLC. Themixture was filtered and the solvent was removed under vacuum. Theresidue was loaded onto a 100 g alumina column packed in ether.Fractions of 50 ml of ether were collected and the desired material wasfound in fraction numbers 3-6. These fractions were combined. Thehydrochloride salt was precipitated and dried, resulting in 5.8 g of1'-[2-[bis(4-fluorophenyl)methoxy]ethyl]-7-fluoro-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride(10.9 mmole, 62.64%). The material appeared pure by TLC on silica gel indichloromethane:methanol (9:1), R_(f) =0.6 in hexane: diethylamine(40:3), R_(f) =0.3, MS (ci MH⁺ =498), NMR-DMSO-d₆ and

IR-CHCl₃ were consistent with the structure; m.p.=165°-168° C.

ANALYSIS. Calculated for C₂₉ H₃₁ ClF₃ NO₃ : 65.22%C, 5.86%H, 2.62%N.Found: 65.24%C, 5.81%H, 2.68%N.

EXAMPLE 441'-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride

The compound2-methylspiro[2H-1,4-benzodioxepin.3(5H)4'-piperidine]hydrochloride (3.3g, 12.2 mmole) was suspended in 100 ml of n-butylacetate along with 3 gof potassium carbonate (milled, anhydrous), 3.8 g of2-[bis(4-fluorophenyl)methoxy]ethyl chloride (13.5 mmole) and 15 mg ofpotassium iodide. The mixture was stirred under nitrogen and heated atreflux overnight. The reaction was determined to be complete by TLC. Themixture was filtered and the solvent was removed under vacuum. Theresidue was loaded onto a 100 g alumina column packed in ether.Fractions of 50 ml of ether were collected and the desired material wasfound in fraction numbers 3-5. These fractions were combined. Thehydrochloride salt was precipitated and was recrystallized from ethylacetate:2-propanol, yielding 3.3 g of1'-[2-[bis(4-fluorophenyl)methoxy]ethyl]-2-methylspiro[2H-1,4-benzodioxepin-3(5H)4'-piperidine]hydrochloride(6.4 mmole, 52.5%) in two crops. This material appeared pure by TLC onsilica gel in dichloromethane:methanol (9:1) R_(f) =0.6 and inhexane:diethylamine (40:3) R_(f) =0.3. MS (ci MH⁺ =480), NMR-DMSO-d₆ andIR-KBr were consistent with the structure; m.p.=179°-181° C.

ANALYSIS Calculated for C₂₉ H₃₂ ClF₂ NO₃ : 67.49%C, 6.26%H, 2.72%N.Found: 67.36%C, 6.23%H, 2.49%N.

What is claimed is:
 1. A compound of formula ##STR36## in which R isselected from the group consisting of a methyl or acetyl group;Hal isfluorine; X is F; and m is zero or
 1. 2. Compound according to claim 1in which R is methyl.
 3. Compound according to claim 1 in which m iszero.
 4. Compound according to clain 1 in which m=1.
 5. A compoundaccording to claim 1 which is1-acetyl-4-ethynyl-4-(2-fluorophenylmethoxy)piperidine.
 6. A compoundaccording to claim 1 which is1-acetyl-4-ethynyl-4-(2,5-difluorophenylmethoxy)piperidine.